chr17-44261630-T-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000342.4(SLC4A1):c.113A>C(p.Asp38Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0386 in 1,614,004 control chromosomes in the GnomAD database, including 1,345 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D38N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.028 ( 100 hom., cov: 32)

Exomes 𝑓: 0.040 ( 1245 hom. )

Consequence

SLC4A1
NM_000342.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.973

Publications

33 publications found

Variant links:

Genes affected

SLC4A1 (HGNC:11027): (solute carrier family 4 member 1 (Diego blood group)) The protein encoded by this gene is part of the anion exchanger (AE) family and is expressed in the erythrocyte plasma membrane, where it functions as a chloride/bicarbonate exchanger involved in carbon dioxide transport from tissues to lungs. The protein comprises two domains that are structurally and functionally distinct. The N-terminal 40kDa domain is located in the cytoplasm and acts as an attachment site for the red cell skeleton by binding ankyrin. The glycosylated C-terminal membrane-associated domain contains 12-14 membrane spanning segments and carries out the stilbene disulphonate-sensitive exchange transport of anions. The cytoplasmic tail at the extreme C-terminus of the membrane domain binds carbonic anhydrase II. The encoded protein associates with the red cell membrane protein glycophorin A and this association promotes the correct folding and translocation of the exchanger. This protein is predominantly dimeric but forms tetramers in the presence of ankyrin. Many mutations in this gene are known in man, and these mutations can lead to two types of disease: destabilization of red cell membrane leading to hereditary spherocytosis, and defective kidney acid secretion leading to distal renal tubular acidosis. Other mutations that do not give rise to disease result in novel blood group antigens, which form the Diego blood group system. Southeast Asian ovalocytosis (SAO, Melanesian ovalocytosis) results from the heterozygous presence of a deletion in the encoded protein and is common in areas where Plasmodium falciparum malaria is endemic. One null mutation in this gene is known, resulting in very severe anemia and nephrocalcinosis. [provided by RefSeq, Jul 2008]

SLC4A1 Gene-Disease associations (from GenCC):

autosomal dominant distal renal tubular acidosis
Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
hereditary spherocytosis type 4
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
renal tubular acidosis, distal, 4, with hemolytic anemia
Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
southeast Asian ovalocytosis
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
dehydrated hereditary stomatocytosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hereditary spherocytosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
cryohydrocytosis
Inheritance: Unknown, AD Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

SLC4A1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0024415255).

BP6

Variant 17-44261630-T-G is Benign according to our data. Variant chr17-44261630-T-G is described in ClinVar as Benign. ClinVar VariationId is 255903.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0692 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC4A1	NM_000342.4 link	c.113A>C	p.Asp38Ala	missense_variant	Exon 4 of 20	ENST00000262418.12	NP_000333.1	P02730-1
SLC4A1	XM_011525129.3 link	c.113A>C	p.Asp38Ala	missense_variant	Exon 4 of 19		XP_011523431.1
SLC4A1	XM_011525130.2 link	c.113A>C	p.Asp38Ala	missense_variant	Exon 4 of 18		XP_011523432.1
SLC4A1	XM_005257593.6 link	c.-83A>C		5_prime_UTR_variant	Exon 2 of 18		XP_005257650.1	P02730-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLC4A1	ENST00000262418.12 link	c.113A>C	p.Asp38Ala	missense_variant	Exon 4 of 20	1	NM_000342.4	ENSP00000262418.6	P02730-1
SLC4A1	ENST00000399246.3 link	c.113A>C	p.Asp38Ala	missense_variant	Exon 4 of 15	5		ENSP00000382190.3	A0A0A0MS98
SLC4A1	ENST00000471005.5 link	n.47A>C		non_coding_transcript_exon_variant	Exon 2 of 4	3
SLC4A1	ENST00000498270.1 link	n.394A>C		non_coding_transcript_exon_variant	Exon 3 of 4	5

Frequencies

GnomAD3 genomes

AF:

0.0282

AC:

4294

AN:

152034

Hom.:

100

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00887

Gnomad AMI

AF:

0.0857

Gnomad AMR

AF:

0.0280

Gnomad ASJ

AF:

0.0271

Gnomad EAS

AF:

0.0754

Gnomad SAS

AF:

0.0350

Gnomad FIN

AF:

0.00659

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0385

Gnomad OTH

AF:

0.0354

GnomAD2 exomes

AF:

0.0339

AC:

8517

AN:

251436

AF XY:

0.0350

show subpopulations

Gnomad AFR exome

AF:

0.00763

Gnomad AMR exome

AF:

0.0187

Gnomad ASJ exome

AF:

0.0277

Gnomad EAS exome

AF:

0.0841

Gnomad FIN exome

AF:

0.00753

Gnomad NFE exome

AF:

0.0385

Gnomad OTH exome

AF:

0.0394

GnomAD4 exome

AF:

0.0396

AC:

57946

AN:

1461852

Hom.:

1245

Cov.:

AF XY:

0.0398

AC XY:

28942

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.00744

AC:

249

AN:

33480

American (AMR)

AF:

0.0203

AC:

909

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0262

AC:

685

AN:

26134

East Asian (EAS)

AF:

0.0655

AC:

2602

AN:

39698

South Asian (SAS)

AF:

0.0396

AC:

3417

AN:

86258

European-Finnish (FIN)

AF:

0.00996

AC:

532

AN:

53420

Middle Eastern (MID)

AF:

0.0630

AC:

363

AN:

5766

European-Non Finnish (NFE)

AF:

0.0420

AC:

46673

AN:

1111976

Other (OTH)

AF:

0.0417

AC:

2516

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

3162

6324

9487

12649

15811

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1816

3632

5448

7264

9080

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0282

AC:

4293

AN:

152152

Hom.:

100

Cov.:

AF XY:

0.0267

AC XY:

1989

AN XY:

74412

show subpopulations

African (AFR)

AF:

0.00884

AC:

367

AN:

41498

American (AMR)

AF:

0.0279

AC:

427

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.0271

AC:

AN:

3470

East Asian (EAS)

AF:

0.0754

AC:

390

AN:

5174

South Asian (SAS)

AF:

0.0346

AC:

167

AN:

4824

European-Finnish (FIN)

AF:

0.00659

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0385

AC:

2614

AN:

67972

Other (OTH)

AF:

0.0360

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

211

422

633

844

1055

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

150

200

250

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0374

Hom.:

400

Bravo

AF:

0.0302

TwinsUK

AF:

0.0396

AC:

147

ALSPAC

AF:

0.0423

AC:

163

ESP6500AA

AF:

0.00931

AC:

ESP6500EA

AF:

0.0372

AC:

320

ExAC

AF:

0.0345

AC:

4188

Asia WGS

AF:

0.0610

AC:

211

AN:

3478

EpiCase

AF:

0.0378

EpiControl

AF:

0.0400

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Nov 08, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal dominant distal renal tubular acidosis

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary spherocytosis type 4

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hemolytic anemia

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.62

CADD

Benign

0.64

(source)

DANN

Benign

0.11

DEOGEN2

Benign

0.17

T;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0071

LIST_S2

Benign

0.083

T;T

MetaRNN

Benign

0.0024

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.4

L;.

PhyloP100

-0.97

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.44

N;.

REVEL

Benign

0.086

Sift

Benign

0.43

T;.

Sift4G

Benign

0.73

T;T

Polyphen

0.0

B;.

Vest4

0.13

MPC

0.44

ClinPred

0.0013

GERP RS

-5.7

Varity_R

0.031

gMVP

0.17

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over